6-cyano androstane derivatives



ilnited States ,atent @hice BfilifiM Patented Dec. 25, 196i The presentinvention relates to certain new cyclopentanoperhydrophenanthrenederivatives.

More particularly, it relates to the novel 6-cyano androstanederivatives, and especially to 6a-cyano-tcstosterone,oot-cyano-l-dehydro-testosterone, 6-cyano-6-dehydro-testosterone, and6-cyano-l,6-bis-dehydro-testosterone, which may further have in theirmolecules substituents such as llfl-hydroxyl, ll-keto,9cx-fiuoro-l1/3-hydroxy, 9a-fluoroll-keto, as well as to the l7ix-alkyl,alkenyl, and alkinyl derivatives of all or" the aforesaid compounds.

Our invention also comprises the novel 6-cyano-derivatives of19-nor-androstane, and more specifically 6acyano-l9-nor-testosterone andits 17ot-alkyl, alkenyl, and alkinyl derivatives, 6OL-Cy3l'lO-l1/3-hydroxy-19-nor-testosterone, 6a-cyano-1l-keto-l9-nor-testosterone,6a-cyano- 1l-keto-17a-methyl-l9-nor-testosterone. Finally it alsocomprises the 17-esters of all of the aforesaid compounds according toour invention.

Among such compounds, those unsubstituted or having an alkyl group atC17CL are anabolic agents having a favorable anabolic-androgenic ratio;those having an alkenyl or alkinyl group at Cl7ot are potentprogestational hormones.

The following general formulas illustrate the new compounds which arethe object of the present invention:

and

OH =0, and

Z is a carbon-to-carbon linkage selected from the group consisting of CCand C=C; R is a member of the group consisting of hydrogen, lower alkyl,lower alkenyl and lower alkinyl radicals, and R is a member of the groupconsisting of hydrogen and acyl radicals derived from hydrocarboncarboxylic acids having up to about 12 carbon atoms.

R comprises lower alkyl radicals such as methyl, ethyl, propyl,isopropyl, the several isomers of butyl and the like up to radicalshaving about 7 to 8 carbon atoms; it further comprises alkenyl radicalssuch as vinyl, propenyl, and alkinyl radicals such as ethinyl, propinyland butinyl.

R, when acyl, is derived from hydrocarbon carboxylic acids the moleculesof which are saturated or unsaturated, of straight, branched, cyclcic ormixed aliphaticcyclic chain, and optionally substituted with functionalgroups such as hydroxyl, acyloxy (of 1 to 12 carbon atoms), alkoxy(formed with lower alkphatic alcohols of 1 to 5 carbon atoms, aromaticalcohols or mixed aliphatic-aromatic alcohols) or halogen such asfluorine or chlorine; typical esters of such acids are, among others,the acetate, propionate, iso-butyrate, hemisuccinate, enanthate,caproate, benzo-ate, trimethylacetate, phenoxyacetate, phenylpropionate,cyclopentylpropionate and fi-chloropropionate.

For preparing the new compounds according to the present invention, Weuse a process which is illustrated in in more detail thereafter:

REACTION DIAGRAM I CH: OH:

OH OH ketalizntion O ethyleneglycol (1) {alkalidmetal cyam 8 O O O: (2)hydrolysis I:

IV IIIA IIIB In the above formulas R, X and Y have the same meaning asexplained hereinbefore, and E is a member of the E a group consisting ofhydrogen and methyl. lm a 1m According to the above-illustrated processa known Y A -3-ketone of the androstane series and having the generalFormula I is first ketalized at C-3 to the correspond- Eenedioxy-Safia-oxidu derivative (IIIA) and then sepa- 1 rated byconventional methods from the accompanying 3-ketal (II) and the latteris then converted into its 3-alkyli stereoisorner (IIIB). By refluxingthe intermediate (IIIA) with an excess of potassium cyanide in mixtureON with ethyleneglycol there is obtained a mixture of the V VII Y-3ralky yand Of the By refluxing compound IV with selenium dioxide in YY- Y)- Which mixture is then mixture with t-butanol, in the presence ofcatalytic Subjected to an add treatment, P y y efluxing amounts ofpyridine and under an atmosphere of nitrogen with dilute sulfuric acidin methanol solution. Thereby we obtain the 1,4 f general Formula In they of general Formula IV is order to introduce a double bond at C-6, wetreat the tained in mixture with its enolic tautomer. A -3-ketones (IV)or the A -3-ketones (V) fir t i n the y of the ahdmstahe Semis butanolsolution with 1.1 molar equivalents of sodium we further introducedadditional double bonds at one or methoxide which reaction produces the5- i both of the PositiOhS C4 and y process steps compound; the latteris reacted directly, without prior isotrated in t e fOllowlhg ReactionDlagfam II: lation, with 1.1 molar equivalents ofbromine; thus WeREACTION DIAGRAM H obtain a 6-cyano-6-bromo compound which isdehydrobrominated by refluxing with -collidine or by reaction 011 withcalcium carbonate. The resulting 6-cyano-4,6-dienes and the6-cyano-l,4,6-trienes are represented by Formulas VI and VIIrespectively.

Ln Y X X We further esterified the 175-hydroxyl group of the E Eabove-menfioned compounds IV by methods commonly d h d employed for thisoperation, which can be illustrated by g g ggthe following equation: 0

$603 I OAcyl CN OH m Iv 1 i h id tb t 1 v Y Y lth lz ano z E [IX Z E x'y-collidine or (321003 esterification in which E, R, X, Y and 2'. havethe same meaning as explained hereinbefore. A is selected from the groupconsisting of (|I@-CI and ()B=C1- cN JN The aforementioned reactions canbe modified within wide limits without altering the result of theprocess. To name some of the possible modifications: the potassiumcyanide may be substituted by another source of cyanide ions, such asfor example sodium cyanide, and/or the ethyleneglycol may be substitutedby another solvent inert to this reaction, preferably having a similarboiling point as ethyleneglycol; the m xture of compounds obtained bythe reaction with the cyanide in ethyleneglycol may be separated bychromatography and the separate components may each be treated with dryhydrogen chloride; this acid may be replaced by another acid, and thereaction may also be elfected with dry hydrogen chloride in acetic acidsolution; the hydroxyl group of the oa-cyauo compounds may be esteriiiedbefore efiecting the dehydrogenation at C-1 and in this case there isobtained the 17-ester of the respective l-dehydro compound; thedehydrogenation at C-1 may also be carried out by microbiologicalmethods, for example by incubation with Corynebacterium simplex ATCC6946.

Furthermore, the 6-dehydro-17u-alkenyl compounds can be obtained bypartial catalytic hydrogenation of the alkinyl group of the-cyano-alhinyl compounds, in pyridine solution and in the presence ofpalladium on calcium carbonate as a catalyst.

Our invention will be further illustrated but not limited in scope by anumber of examples:

Example 1 A mixture of 6 g. of testosterone, 120 cc. of dry benzene, 45cc. of ethyleneglycol distilled over sodium hydroxide and 800 mg. ofp-toluenesulfonic acid monohydrate was refluxed for 12 hours with theuse of a Water separator; the cooled mixture was treated with aqueoussaturated sodium bicarbonate solution, and the organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate,filtered, and the solvent was evaporated under reduced pressure. Theresidue was purified by chromatography on neutral alumina, thus yielding3-ethylenedioxy-A -androsten-l7,8-01.

A cooled solution of 5 g. of the above lretal in 100 cc. of chloroformwas treated with an ether solution of monoperphthalic acid containing1.2 molar equivalents of the reagent and the mixture was kept at roomtemperature in the dark for 24 hours; the mixture was then diluted withwater, and the organic layer was separated, washed with water, driedover anhydrous sodium sulfate and the solvent was evaporated underreduced pressure. T he residue consisted of a m xture of3-ethylenedioxy-5 om-oxido-antrostan-flfi-ol and3-ethylenedioxy-55,6/3-oxidoandrostan-17,B-ol, wherefrom the 502,601.isomer was isolated by chromatography on neutral alumina.

A mixture of 5 g. of 3-ethylenedioxy-5u,6a-oxido-androstan-17fi-o1 (3-cycloethyleneketal-Sa,6d-epoxide of testosterone), g. of potassiumcyanide and 200 cc. of ethyleneglycol was refluxed for 1 hour, pouredinto ice water and the precipitate was collected, thus giving a mixtureof the 3-hydroxyethyl ether of 6-cyano-A -androstadiene 3,17,8-diol andof 6-cyano-3ethylenedioxy-M-androsten-17,8-ol. The precipitate waswashed with water, air dried, mixed with 250 cc. of methanol and 25 cc.of 8% (v./v.) sulfuric acid and refluxed for 36 minutes. The cooledmixture was diluted with 250 cc. of water, the methanol was distilledunder reduced pressure and the mixture was neutralized with saturatedaqueous sodium bicarbonate solution; the product was extracted withmethylene chloride and the extract was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness. Crystallization ofthe residue from acetonehexane afforded 6-cyano-testosterone.

Example 2 A solution of 5 g. of A -dehydro-testosterone (n-androstadiene-17,8-ol-3-one) [described by F. W. lieyl et al. in JACS77, 488 (1955)], in 50 cc. of pure dioxane containing 8 cc. of 0.4normal perchloric acid was treated at room temperature in the absence oflight with 2.5 g. of N-bromo-acetamide which was added under stirring inthe course of one hour; the mixture was stirred for another hour andtreated with 10% sodium sulfite solution until the test withstarch-potassium iodide paper failed to give a blue color; 75 cc. ofchloroform were then added, the resulting organic layer separated andsuccessively washed with water, sodium bicarbonate solution and againwith water, then dried over anhydrous sodium sulfate and the solventevaporated to dryness under vacuum. Trituration of the residue withether yielded 9oi-bromo-A -androstene-1lfl,17fi-diol-3-one.

A solution of 4 g. of the aforesaid compound in 20 cc. of pure dioxanewas slowly added to a mixture of 2 g. of potassium acetate in 40 cc. ofabsolute ethanol, which had been previously heated to the boiling point.The mixture was refluxed for 45 minutes, cooled and diluted with Waterand the precipitate collected by filtration, washed with water anddried, thus giving the 9fl,l1;5-oxido-A -androstene-17,B-ol-3-one.

In a polyethylene flask, fitted with a magnetic stirrer, 2 g. ofcompound ill was dissolved in 40 cc. of pure chloroform, the solutionwas cooled to 0 C. and mixed in the course of 20 minutes, whilestirring, with 0.4 g. of anhydrous hydrogen fluoride. The mixture wasstirred for 2 hours at 0 C. and then neutralized by cautious addition ofaqueous sodium bicarbonate, the reaction mixture was transferred to aseparatory funnel, washed with water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure until precipitation;the mixture was cooled and the precipitate collected; afterrecrystallization from acetone-hexane, 9rx-fill01'0-l1B-hydroxy-testosterone is obtained.

The latter compound was further treated as described in Example 1 andthere were obtained 3-ethylenedioxy- 9oi-fluoro-A -androstene-11,8,17/3-diol; S-ethyienedioxy-Sa, 6oc-0Xld0- and3-6thy1el1diOXy-5,8,6fi-OXld0-9r4-fit10IO-Ztlldrostane-11fl,l7/3-diols;the 3-hydroxyethyl ether of 6- cyano-9d-fluoro-M-androstadiene-3,llfi,17fitriol and 6- cyano 3 ethylenedioxy fiuoro Aandrostene- 11,8,17ddio1, and finally6a-cyano-9u-iluoro-1lfi-hydroxytestosterone.

Example 3 The following solutions A, B and C were prepared usingdistilled Water as solvent: solution A was prepared by mixing 425 cc. ofa 1.742% dipotassium hydrogen phosphate solution (K HPOQ with 75 cc. of1.38% monosodium dihydrogen phosphate; solution B was prepared bydiluting a mixture of 1 it. of 4.5% sodium chloride solution, 40 cc. ofa 5.75% potassium chloride solution and 10 cc. of a 19.1% magnesiumsulfate, to a volume of 5 1t; solution C was prepared by dissolving 20.9g. of fumaric acid and 14.4 g. of sodium hydroxide in 1 It. of water anddiluting the solution to 1.2 It. Then 475 cc. of solution A, 4.32 It. ofsolution B and 1.2 It. of solution C were mixed.

The fat was removed from the adrenal glands obtained from recentlyslaughtered oxen and the glands were ground in a meat grinder until anhomogeneous mass was obtained; 3 kg. of this mass were then added to 6It. of the mixture of solution A, B and C, obtained as described above,and the mixture was vigorously stirred.

There was then added 3 g. of 17a-ethinyl testosterone in 16 cc. ofpropylene glycol and the mixture was stirred again at a temperature of2837 C. for 3 hours. 40 lt. of acetone was then added and the stirringwas continued for one hour further at room temperature.

The solid was removed by filtration and washed twice with 10 1t.fractions of acetone; the washings were combined with the filtrate andconcentrated under reduced pressure below 30 C. to a volume ofapproximately It The aqueous residue was washed three times with 4 it.portions of hexane and the hexane was discarded. The aqueous residue wasthen extracted with 2 portions of 3 It. of methylene dichloride, theextract was washed with water, dried over anhydrous sodium sulfate, andconcentrated to a volume of approximately 300 '00., under vacuum andbelow room temperature.

The concentrated solution was allowed to pass through a column preparedwith a mixture of 90 g. of silica and 90 g. of celite. The column waswashed with 3 it. of methylene dichloride and then with a mixture of 900cc. of methylene dichloride and 100 of acetone. The product was theneluted with mixtures of methylene dichloride and acetone (80:20 and70:30). The solvents from these elutions was evaporated and the residuecrystallized from ethyl acetate. There was thus obtainedl7a-ethinyl-l1ehydroxy-testosterone.

The latter compound was then further treated as described in Example 1,and there were obtained the 3-ethylenedioxy derivative, a mixture of theS-ethyIenedioXy-Sa, 6a-oxido and the 3-ethylenedioxy-5B,6{i-oxidoderivatives, the 3-hydroxy ethyl ether of the 6-cyano-A -androstadienecompound and the 6-cyano-3-ethylenedioxy-A -androstene compound derivedfrom l7a-ethinyl-1lfl-hy droxytestosterone, and finally6ot-cyano-l7ot-ethinyl-l l5- hydroxytestosterone.

Example 4 500 mg. of llfi-hydroxy-l9-nor-testosterone, described inUnited States Patent 2,655,518, were mixed with 5 cc. of pyridine and 2cc. of acetic anhydride and allowed to stand at room temperature for 4hours. The mixture was then poured into ice water and filtered, theprecipitate was washed with water and recrystallized from acetonehexanethus giving the acetate of llB-hydroxy-nor-testosterone.

300 mg. of the above product were dissolved in 5 cc. of acetic acid andtreated with a solution of 72 mg. of chromic acid (1.2 mol equivalents)in 3 cc. of 80% acetic acid, the reaction mixture let stand at roomtemperature for 1 hour, poured into ice water, the precipitate wascollected and washed with water until neutral. After crystallizationfrom acetone-ether, ll-keto-nor-testosterone acetate was obtained. Thiscompound (210 mg.) was dissolved in 10 cc. of methanol, and a solutionof '70 mg. of sodium hydroxide in methanol (2 cc.) was added and thereaction mixture let stand under nitrogen for 1 hour at roomtemperature, after this time it was neutralized with a few drops ofacetic acid, and the solution concentrated to one-third its volume underreduced pressure, poured into ice water, the precipitate was filteredthus giving the free l1-keto-l9-nor-testosterone.

Further processing of the latter compound by the method described inExample 1 leads ultimately to 60t-CYBI10- 1 l-keto-l9-nor-testosterone.

Example 5 l g. of 9a-fluoro-ll-keto-testosterone described in RecentProgress in Hormone Research, vol. XIV (1958), and US. Patent 2,678,933,was dissolved in cc. of acetic acid and treated at room temperature witha solution of 240 mg. (1.2 mol equivalents} of chromic acid in 5 cc. of80% acetic acid; the reaction mixture let stand at room temperature for1 hour, poured into ice water, the precipitate collected, washed withwater until neutral and recrystallized from methylene in chloride-ether,thus yielding 9a-fluoro adrenosterone.

A suspension of l g. of the above compound in 10 cc. of peroxide-freedioxane and 2 cc. of freshly distilled ethyl orthoformate was treatedwith 30 mg. of p-toluenesulfonic acid monohydrate and the reactionmixture stirred at room temperature for 4.5 minutes (the solid came intosolution within 20 minutes). After this time,

the resulting yellow solution was treated with 0.8 cc. of pyridine andpoured into ice water; after filtration of the precipitate andrecrystallization from methanol-water, the 3 enol ether of9a-fluoro-adrenosterone was obtained.

Into a solution of 800 mg. of 9a-fluoro-adrenosterone in cc. of 3:2benzene-anhydrous ether was passed a slow stream of acetylene for 1hour. With continued stirring, a solution of 0.8 g. of potassium in- 35cc. of purified tert-amyl alcohol Was added rapidly and the stream ofacetylene continued for 3 hours more. After this time, the system wasflushed with nitrogen, the reaction mixture diluted with benzene andtreated cautiously with 200 cc. of saturated aqueous ammonium chloride.The organic layer was separated and the aqueous phase was reextractedthree times with benzene, the combined extracts were washed withsaturated ammonium chloride solution and water; dried over anhydroussodium sulfate and evaporated to dryness with vacuo; the crude enolether was dissolved in 50 cc. of methanol, 5 cc. of 0.25 N hydrochloricacid added and the faintly turbid suspension let stand at roomtemperature overnight, poured into ice water and the precipitatecollected. Recrystallization from methylene chloride-ether (afterdecolorization with charcoal) yielded the pure Que-fluoro- 1 1-ketol7zx-6thi11Yl-IEStOStC1'OIl6.

The latter compound was treated by the method described in Example 1 andthere was ultimately obtained 6a-cyano-9a-fluoro-1l-lreto-17a-ethinyltestosterone.

A solution of 500 mg. of the last mentioned compound in 15 cc. ofpyridine was shaken in hydrogen with 0.2 g. of a 5% palladium-on-calciumcarbonate catalyst at atmospheric pressure and room temperature; after 1mol of gas had been absorbed and the uptake had become slow, thecatalyst was removed, the solvent was evaporated in vacuo and theresidue was dissolved in ethyl acetate. Washing with dilute hydrochloricacid, sodium bicarbonate and water, drying with anhydrous sodium sulfateand finally crystallization from ethyl acetate furnished6a-cyano-9ix-fluoro-1l-keto-l7a-vinyl-testosterone, 7\ max. 238 mu, logE 4.12.

Examples 6-33 The method of the preceding examples was applied toprepare first the 3-ethylenedioxy-5a,6a-oxido derivatives of thetestosterone analogs cited in Table I below used as starting materials,and there was obtained the respective 6tz-eyano-A -3-ketones listed inthe same table:

TABLE I Example Starting Material Source of Starting GQ-cyano productNo. Compound 6 l7a-n1ethyl-tes- \velllznown and fia-cyano-l'latosteroue.conventional. methyl-testostel-one. -7 17a-ethyl-testosdooa-cyano-liaterone. ethyl-testosterone. 8 l7a-vinyl-testos- .doGoz-CYtillO-l'laterone. vinyl-testosterone. 9 l7a-etllinyl-tesdofia-cyanodiatosterone. ethinyl-testosteronc. 1017a-propin'(1)-ylprepared with the da-eyano-fla-protestosterone. aid ofpropinepin-(l)-yl-tes- (l) by the tosterone. method described by Ruzickaat 9.1., Helv. Chim. Acta 20, 1280 (1937 11 lldhydroxytes- Fried et 21.,dot-cyano-llfi-hytosterone. .T.A.O.S. 74, droxy-testos- 3692 (1952).terone. l2 19-nor-testoswell known and fia-cyano-la-norterone.conventional. testosterone. 13 17ct-HlBllhYl-1l- J. Biol. Chem.(ia-eyanQ-Uakcto-tostos- 228, 339 (1957), methyl-ll-ketoterone. U.SPatent testosterone.

Example Starting Material Source of Starting (Sq-cyano product NO.Compound I 14 9a-fiuoro-11-keto- Recent Progress Gzx-CYBHO-Qa-fillOlO-testosterone. in Hormone ll-keto-testos- Research, vol. terone. XIV(1958), U.S. Patent 2,793,218.

15 17a-D1Gtl1Yl-9- U.S. Patent 6a-eyano-17crfluoro-llfi-hy- 2,793,218and methyl-9adroxytestoS- Herr et al., fiuoro-llfi-hyterone. .TAOS 78,500 droxy-t estos- (1956). terone.

16 ll-keto-testos- Mono-era et a1., da-eyano-ll-ketoterone. .TACS 75,2189 testosterone.

17 QwfiIIOIO-l'la- U.S. Patent 6a-oyano-9amethy111-keto- 2,793,218.tluoro-170r-methyltestosterone. 11-keto-testosterene.

18 11-"eto-17 z- U.S. Patent fia-cyano-ll ketomethyl-'l9-nor- 2,678,933.17a-mcthyl-19- testosterone. nontestosterono.

19 llfl-hydroxy-IQ- U.S. Patent (ia-eyono-llflnor-testosterone.2,655,518. hydroxy-lO-nortestosterone.

20 11B-hydroxy-17a- US. Patent 6a-oyeno-11flmethyl-le-nor- 2,686,792.hydrow-lmtestosterone. methy1-19-nortestosterone.

21 llfi-hydroxy-l'ia- U.S. Patent Ga-cyano-llflvinyl-19-nor- 2,702,811.hydroxy-lfiztestosterone. vinyl-le-nortestosterone.

22 llfi-hydroxy-lm- U.S. Patent 6a-eyano-115- thinyl-19- 2,702,811.hydroxy-17anor-testosterone. ethinyll9nortestosterone.

23 ea-fluoro-n-keto- U.S. Patent (ia-eyano-flalo-nor-testos- 2,838,503.fluoro-lldretoterone. lg-nor-testosterone.

24 9a-fluoro-11B- U.S. Patent 6a-eyano-9ahydroxy'l -nor- 2,838,503.fiuoro-llfi-hytestosterone. droxy-lQ-nortestosterone.

25 Qa-fiuoro-llfi- U.S. Patent Ga-eyano-Qw hydroxy-lh- 2,793,218.fiuoro-ilBhymethy1-19-nordrew-17atestosterone. methyl-lonertestosterone.

26 Qa-fluoro-ll-keto- U.S. Patent 6a-eyano-La- 17zx-methy119- 2,838,503.fiuoro-1ll etonor-testosterone. 17d-methy1-19- nor-testosterone.

27 Qa-fluoro-Hfi- U.S. Patent oa-cyano-eahydroxy-Ua- 2,836,607.fluoro-llB-hyvinyl-19-nordrew-17atestosterone. vinyl-le-nortestosterone.

28 17a-vinyl-11-ketoprepared from Goa-CYHDG-l'lal -nor-testos- .llflhydroxyvinyl-ll-lretoterone. le-nor-testos- 19-nor-testosterone by theterone. methods of Examples 4, 5 and 29 17a-ethinyl-11- prepared fromda-eyano-lmketo-lQ-nor- 11B-hydroxyethinyl-11-ketotestosterone.lo-nor-testosl -nor testosterone by the terone. methods of Examples 4and 5.

30 17u-methyl-1a Djerassi et al., 6a-eyano-17anor-testosterone. .T.A.(IS. 76, methyl-loner- 4092 (1954). testosterone.

31 17a-ethinyl-19- Djerassi et al., 6n-eyano-17anor-testosterone.ibidem. ethinyblQ-nortestosterone.

32 l7a-vinyl-19-nor- Djerassi et al., 6a-eyano-17atestosterone. J.A.C.S.77, vinyl-17a- 148 (1955). ethinyl-lQ-nortestosterone.

Example 33 A mixture of '3 g. of a cyano-testosterone prepared asdescribed in Example 1, 250 cc. of t-butanol, 1.6 g. of

selenium dioxide (recently sublimed) and a few drops of pyridine wasrefluxed under an atmosphere of nitrogen for 48 hours and filteredthrough celite; the filtrate was evaporated to dryness, the residue wasdissolved in acetone, treated with decolorizing charcoal, refluxed for 1hour, filtered and the acetone was evaporated. Chromatography of theresidue on neutral alumina yielded 6a-cyano-A-androstadien-17fi-ol-3-one.

Example 34 The method of dehydrogenation of the preceding example wasapplied to the oa-cyano-derivatives of (a) 17amethyl-testosterone, (b)lia-propyl-testosterone, (c) 17avinyl-testosterone, (d)17a-propinyl-testosterone, (e) 11- keto-testosterone, and (f)17a-methy1-1lfi-hydroxy-testosterone; there were thus obtained therespective 6OL-CY- ano-A -3-ketones, namely: (a) 6a-cyano-17ot-methyl-ALandrostadien-17,8-01-3-one; (b) 6a-cyano-17a-propyl-Aandrostadien-l7fl-ol 3-one; (c) 6bz-cyano-17a-vinyl-Aandrostadien-17fi-ol-3-one; (d) 6a cyano 17a propinylo-androstadien-17fi-ol-3-one; (e) 6a-cyano-A-androstadien-17/3-ol-3,1l-dione; and (f) 6ot-cyano-17a-methyl- A-androstadien-llfl, 17,8-dio1-3-one.

Example 35 A solution of 4 g. of 6a-cyano-testosterone prepared 'asdescribed in Example I, in 120 cc. of t-butanol was added to 1.1 molarequivalents of sodium methoxide, prepared by removing the solvent from amethanol solution of the corresponding amount of sodium metal; themixture was stirred at room temperature for half an hour and then therewas slowly added under stirring a solution of 1.1 molar equivalents ofbromine in t-butanol, while maintaining the temperature at around 15 C.The mixture was kept for half an hour at room temperature, diluted withWater and the precipitate was collected by filtration, Washed with waterand dried under vacuum. The product, namely the crude6-cyano-6-bromo-testosterone, was used for the next step Without furtherpurification.

A solution of the above compound in 20 cc. of dimethylformamide wasadded to a hot suspension of 1.5 g. of calcium carbonate indimethyl-formamide and the mixture was refluxed for 15 minutes,concentrated to about 20 cc., cooled and poured into aqueous saturatedsodium chloride solution; the precipitate was collected, washed withwater, dried and recrystallized from acetone-hexane. There was thusobtained o-cyano-6-dehydro-testosterone.

Example 36 A mixture of 2 g. of 6-cyano-6-bromo-testosterone, theintermediate obtained in the preceding example, and 50 cc. of'y-collidine was refluxed for 1 hour, cooled, diluted with ether and theprecipitate of collidine hydrobromidc was removed by filtration; thefiltrate was washed with dilute hydrochloric acid, then with aqueoussaturated sodium bicarbonate solution and finally with water, dried overanhydrous sodium sulfate and the ether was evaporated. The residuecrystallized from acetone-hexane to produce6-cyano-o-dehydro-testosterone, identical with the final product of thepreceding example.

Example 37 In accordance with the meLhod described in.-Examples 35 and36, there was introduced an additional double bond at C-6 or (a)Gu-cyano-l-dchydro-testosterone, (b) 601-cyano-17a-ethinyl-testostcrone, (c) 60: cyano 11 ketotestosterone, (d)17a-methyl-6u-cyano-1lfl-hydroxy-l-dehydro-testosterone and in (e)6a-cyano-17ot-methyl-9m-fluoro-I lfl-hydroxy-testosteronc and (f)17ot-methyl-6ct-c'yano-testosterone. The resulting products were: i

Example 38 A mixture ofl g. of oa-cyano-testosterone prepared asdescribed in Example 1, 5 cc. of pyridine and 1 cc. of

ll acetic anhydride was kept overnight at room temperature and thenpoured into water and heated on the steam bath for half an hour; aftercooling, the precipitate was collected, washed with water, dried andrecrystallized from acetone-hexane. There was thus obtained the acetateof 6u-cyano-testosterone.

Example 39 There was prepared 6-cyauo-l,6-bis-dehydro-testosterone byintroducing a double bond at C6 of Ga-cyano-ldehydro-testosterone, inaccordance with Example 37(a); 1 g. of this triene was treated with 5cc. of pyridine and 2 cc. of propionic anhydride and kept overnight atroom temperature; the reaction mixture was poured into water and theprecipitate was collected, washed with water, dried and recrystallizedfrom acetone-hexane, thus furnishing the propionate of6-cyano-1,6-bis-dehydro-testosterone.

Example 40 A mixture of 1 g. of 6a-cyano-l7a-methyl-ll-keto-testosteroneprepared as described in Example 13, 25 cc. of acetic anhydride and 5 g.of acetyl chloride was refluxed under an atmosphere of nitrogen for 2hours. The solvent was removed by distillation under reduced pressure,avoiding overheating, and the residue was treated with 50 cc. of 1%methanolic potassium hydroxide solution and stirred under an atmosphereof nitrogen at C. for 1 hour. The mixture was acidified with aceticacid, concentrated to about 10 cc. poured into cold aqueous sodiumchloride solution; the precipitate was collected, washed with water,dried and recrystallized from acetonehexane. There was thus obtained thel7-acetate of 6c:- cyano-l7a-methyl-l l-keto-testosterone.

. 7 Example 41 A solution of 1 g. of 17oc-BthlI1Yl-6a-CY3HO-19-110r-5-dehydrotestosterone prepared by the method described in Example 35 fromthe end product of Example 32, in 100 cc. of benzene was treated with 3cc. of benzoyl chloride and 150 mg. of p-toluenesulfonic acidmonohydrate, stirred for 48 hours at room temperature and diluted withwater; the benzene layer was separated, washed with aqueous sodiumcarbonate solution and then with water to neutral, dried over anhydroussodium sulfate, the benzene was evaporated and the residue crystallizedfrom acetone-hexane. There was thus obtained the benzoate of17u-ethinyl-6-cyauo-19 nor-6-dehydro-testosterone.'

Example 42 A mixture of 1 g. of6a-cyano-9a-fluoro-llfi-hydroxytestosterone, prepared as described inExample 2, 5 cc. of pyridine and 3 cc. of cyclopentylpropionic anhydridewas kept at room temperature for 48 hours, poured into water, heated for2 hours on the steam bath, cooled and the precipitate was collected,Washed with water, dried and recrystallized from acetone-hexane. Therewas thus obtained the 17fl-cyclopentylpropionate of 6e-cyano-9ufluoro-l113-hydroxy-testosterone.

Example 43 12 We claim: 1. A member of the group consisting of the newcompounds corresponding to the general formulas in which X is a memberof the group consisting of hydrogen and fluorine, Y is selected from thegroup consisting of Z is a carbon-to-carbon linkage selected from thegroup consisting of C-C and C=C, R is a member of the group consistingof hydrogen, lower alkyl, lower alkenyl and lower allainyl, and R is amember of the group consisting of hydrogen and the acyl radical of ahydrocarbon carboxylic acid having up to about 12 carbon atoms.

2. A compound as described in claim 1, in which R is lower alkyl.

3. A compound as described in claim 1, in which R is methyl.

4. A compound as described in claim 1, in which R is lower alkenyl.

5. A compound as described in claim 1, in which Ris vinyl.

6. A compound as described in claim 1, in which R is alkinyl.

7. A compound as described in claim 1, in which R is ethinyl.

8. A compound as described in claim 1, in which X is fluorine and Y is=0.

9. A compound as described in claim 1, in which X is fluorine and Y is10. A compound as described in claim 1, in which YiS =0.

11. A compound as described in claim 1, in which Yis 12. A compound asdescribed in claim 1 in which R is the acyl radical of a hydrocarboncarboxylic acid having up to about 12 carbon atoms.

13. 6a-cyano-testosterone.

. 6a-cyano-l-dehydro-testosterone.

. 6-cyano-6-dehydro-testosterone.

. G-cyano-1,6*bis-dehydro-testosterone.

. 6u-cyano-19-nor-testosterone. 6oz-CY3I10-l7oL-(1OW61alkyl)-19-nor-test0stei'one. 6 6a-cyano-17a-(loweralkenyl)-1-9-nor-testosterone.

14 References Cited in the file of this patent UNITED STATES PATENTSOTHER REFERENCES Sanchez et aL: Journal of American Chemical S0-6a-cyano-17a-(1ower alkinyl)-19-nor-testosterone. ciety (1959) VOL 81,pages 52334242 relied on Nobile June 3, 1958

1. A MEMBER OF THE GROUP CONSISTING OF THE NEW COMPOUNDS CORRESPONDINGTO THE GENERAL FORMULAS